initial clinical assessment of the parkinsonian patient · anti alpha syn •aso – •b2-...
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Initial Clinical Assessment of a Parkinsonian Patient
Jill Ostrem, MD
Carlin and Ellen Wiegner Endowed Professor of Neurology
Division Chief and Medical Director
UCSF Movement Disorder and Neuromodulation Center
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Disclosures• Consultant: Medtronic, Abbott
• Educational grant support: Medtronic, Allergan, Boston Scientific, AbbVie, Merz
• Clinical trial support: Boston Scientific, Cala Health, Medtronic, Biogen, Roche, Neuroderm
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Diagnosis of Parkinson’s Disease
• Comprehensive history and physical exam
• No definitive test to confirm PD
• Clinical diagnosis requires review of history, assessment of symptoms, careful examination, rule out alternative diagnosis
• It can take time to work out
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26% accuracy for a clinical diagnosis of PD in untreated or not clearly responsive subjects53% accuracy in early PD responsive to medication (5 years’ duration)85% diagnostic accuracy of longer duration, medication-responsive PD
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Parkinson’s Disease Clinical Features
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MDS Diagnostic Clinical Criteria for PD
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MDS Diagnostic Clinical Criteria for PD
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Common Initial PD Symptoms
• Non-motor – often “Pre-motor”• Loss of sense of smell• Constipation• Sleep disorders – Rapid Eye Movement Behavior Sleep
Disorder (RBD)• Depression
• Motor• Subtle rest tremor in one arm/hand/finger• Sense of stiffness in one limb
• Maybe interpreted as orthopedic problem
• Sense of slowness in one limb• Decreased dexterity, decreased arm swing
• Stooped or slow walking• Decrease blink rate/ softer voice
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Case Mild Parkinsonism• 55 yo male• Initial symptoms right shoulder pain• mild intermittent right hand rest
tremor• RBD, poor smell
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Case of Early PD
• 50 yo male• Initial symptoms mild intermittent right hand>leg
rest tremor• Insomnia, constipation, anosmia, urinary urgency
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Case: Mild Parkinsonism • 61 yo RH male• Initial symptoms mild
intermittent right hand rest tremor followed by toe curling and ankle inversion (foot dystonia)
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Parkinson’s Disease-Slower Rest Tremor
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Parkinson’s Disease
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Parkinson’s Disease
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Parkinson’s Disease- Rigidity
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Parkinson’s Disease- No Tremor
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PD - Postural Instability
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PD Subtypes
jamanetwork.com
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Advanced PD
OFF medication
ON medication
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Scales Used to Access Newly Diagnosed PD(Maybe)
• UPDRS
• MDS-UPDRS
• Hoehn and Yahr – available since 1960’s• Five stages mild to bedridden
• Other scales used• Mood scales ?
• MOCA
• Tremor scales ?
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UPDRS New Version• Parts IA (investigator) and B (patient):
non-motor experiences of daily living• Part II: motor experiences of daily living• Part III: motor exam, on and off• Part IV: motor complications
11
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Assessment of Cognitive Impairment/Dementia
Montreal Cognitive Assessment (MOCA)(range 0-30)
• Characteristics of PD – MCI/D• Less problem with memory,
language (AD)
• Attention, apathy, executive (FRONTAL)
• Fluctuation level of consciousness
• Hallucinations/delusions, visuospatial (PARIETAL/TEMPORAL)
• Score >26 = cognitive impairment
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Assessment of Cognitive Impairment/Dementia
• Parkinson’s Progression Markers Initiative(PPMI)• Multi-site longitudinal study of early, untreated PD patients and HC.
• Baseline, 22% of 423 PD patients met the recommended screening cutoff for cognitive impairment on the MoCA (<26), but only 9% met detailed neuropsychological testing criteria for PD-MCI (level I impairment).
• Estimated rates of MCI might be higher when using a screening instrument versus cognitive test battery, given recommended cut-off scores for screening instruments typically prioritize sensitivity over specificity.
Weintraub D, Simuni T, Caspell-Garcia C, et al. Cognitive performance and neuropsychiatric symptoms in early, untreated Parkinson’s disease. Mov Disord 2015;30:919-927.
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Lab Tests to Consider
• Vit B12, Vit D
• Methomalonic acid
• TSH (thyroid)
• Toxin screening if patient’s history of suggestive of possible exposure
• Measurement of copper or ceruloplasmin may be warranted – role out Wilson’s disease
• Genetic testing
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PD GeneticsGene Mutations Protein/Enzyme Function Age at
onsetPhenotype Pathology
Dominantly inherited last-onset PD
SNCA Missense Alpha synuclein- structural brain protein
60 yr
(30-80)
Levodopa responsive Diffuse lewy bodies
SNCA Locus duplication (and triplication)
31-71 yr Levodopa responsive, younger age, rapid progression, autonomic dysfunction, dementia, wide spread Lewy Bodies
Diffuse lewy bodies, prominent nigral and hippocampal loss
LRRK2 Missense: Arg1441Cys/Gyl/His; Try1688Cys, Gly2019Ser, IIe2020Thr
Polymorphisms, protective haplotypes
Leucine-rich repeat kinase 2- enzyme when mutated causes Lewy-body phenotype –increased kinase activity
60 yrs(32-79)
Levodopa responsive, Like sporadic PD, slow progression, abduction-addition lower limb tremor, little dementia
Brain Stem LB, neurofibrillary tangle or TDP-43 pathology and/or nigral neuronal loss
VPS35 Missense: ASP620Asn 53 yrs(40-68)
Levodopa responsive tremor-dominant, dyskinesia and dystonia, occasionally dementia
Inconclusive- ? No LB
GBA1 Gcase protein activity decreases
51 yrs Levodopa responsive, more dementia Lewy bodies
Juvenile and early-onset recessively inherited PD
PARK2 Numerous missence, exon deletion and duplication mutations
Parkin- a ubiquitin-protein ligase involved in protein degradation
<45yr (12-58)
Levodopa responsive, early dystonia, slow progression, hyperreflexia, dyskinesia, early gait and balance issues, less non-motor
Predominantly nigralneuronal loss
Occasionally with synucleinor tau pathology
PINK1 Misssence: many
Rare: locus and exon deletion
PTEN-induces putative kinase
<45yr (18-56)
Levodopa responsive, akinetic/ridged postural instability, gait, slow progression, sleep benefit
One case with lewy bodies
DJ-1 Misense: Glu163lys, Leu166Pro Exon 1-5 deletion, g.168-185 dup
Positive regulator of androgen- receptor dependent transcription
<40 yr(24-39)
Like PINK-1, rare Unknown
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Parkinsonism Genetic Panels
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Anti alpha syn
• ASO –
• B2- adrenoreceptor against and antagonist drugs and risk of PD 0 Neurology (paper)
• Tyrosine kinase C-abl inhibitors – Nilotinib (poor CNS penetation
• Propagation of alpha synuclen-
• LRRK2
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• Gain of function in LRRK2 to increase the kinase activity and more phosphoralation – RAB10 –failure of autophagy (lysosome)
• Trials : Denali
• ASO coming for this too
• Kinase inhibitors – many- but lots of potential peripheral side effects – lung, kidney, spleen – also increase in some types of cancer
• LRRk2 and Gcase convergence in PD
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GBA
• Do J et al 2019 – good slide
• JR mazzulli J cell 2011 – good slide
• AAV- GBA1 gene
• Venglustat –GCS inhibitor
• Small brain penetrant chaperons - ie ambroxol
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LRRK2 Mutation Parkinsonism
Phenotype
• Like sporadic PD (later
onset)
• Variable clinical and
pathological phenotype
• Levodopa responsive
• Slow progression
• Abduction-addition
lower limb tremor
• Little dementiaVideo Courtesy of Dr. San Luciano and Darel Ogbonna
• Mutation in the leucine rich repeat kinase 2 (LRRK2) gene (G2019S) is the greatest known genetic cause of PD
• Most common monogenic cause of PD in Europe and North America
• Higher in Ashkenazi Jewish families
• 30% penetrance
• Mutations seem to heighten the activity of LRRK2 kinase
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GBA Mutation Parkinsonism
• GBA1 mutations cause dysfunction in the glucocerebrosidase (Gcase) protein-leading to build-up of alpha-synuclein
• More common in Ashkenazi Jewish descent /Gaucher or relative with Gaucher(lipids build up and enlarge organs)
• 5-10 % of PD patients carry this mutation• GBA mutation - 20X increased risk of PD• GBA mutations are common but overall chance of PD is still low
Phenotype• Slightly earlier age of onset• Initial symptom often
bradykinesia• More rapid motor disease
progression, more dyskinesia• More cognitive dysfunction• Less tremor• More depression
Video Courtesy of Dr. San Luciano and Darel Ogbonna
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Parkin Mutation Parkinsonism
Parkin- a ubiquitin-protein ligase involved in protein degradation
Numerous missense, exon deletion and duplication mutations, No LB?
Phenotype:
Younger age onset, levodopa responsive, dystonia, akinetic/ridged, postural
instability, gait, slow progression, sleep benefit Video Courtesy of Dr. Nick Galifianakis
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Other Diagnostic Procedures
• Dopaminergic challenge test
• MRI
• DatScan/18 F-FDG PET
• Neuropsychiatric testing
• Sleep studies- Polysomnogram
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Acute Levodopa Challenge
• Not performed often
• Very likely to cause nausea- would need to pre-medicate (carbidopa/domperidone)
• Serial exams before and after
• 30% improvement in UPDRS III considered positive
• Many false positive and negative results!
• Can help predict long-term chronic response to levodopa
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Structural MRI in Parkinsonism
• Routine brain MRI usually normal in PD• Identify presence of lesions• NPH like picture- MRI r/o hydrocephalus• Lower body PD- r/o vascular PS• Quantify brain atrophy• Red flags on exam - MSA/ PSP• 7T MRI or other scans maybe helpful in the
future
Clinical Medicine 2016 Vol 16, No 4: 371–5
Pagano, Niccolini, and Politis
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DatScan Mechanism & Indications
INDICATIONS AND USAGEDaTscan is a radiopharmaceutical indicated for striatal dopamine transporter visualization using single photon emission computed tomography (SPECT) brainimaging to assist in the evaluation of adult patients with suspected Parkinsoniansyndromes (PS).
DaTscan may be used to help differentiate essential tremor from tremor due to parkinsonian syndrome
Bajal, 2013; FDA Product Label
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DatScan
Helpful:
• Essential tremor (nl) from parkinsonian tremor (abnl) (presynaptic dopaminergic deficit)
• Drug induced parkinsonism (nl) from PD (abnl)
• Alzheimer's disease (nl) from Lewy body dementia (abnl)
• Normal from Premotor phase PD (abnl) (clinical trials)
Not helpful:
• PD (abnl) from MSA or PSP (abnl)
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Who Makes Diagnosis and Team Involved
• Primary Care Physician
• Family Practice Physician
• Neurologist
• Movement Disorders Specialist
• Team: Nurse, Social worker, Psychologist, Physical Therapist, Neuropsychologist, Neurosurgeon, Genetic Counselor
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UCSF Movement Disorders
NeurosurgeryPhilip Starr, MD, PhDPaul S. Larson, MDDoris Wang, MD, PhDDaniel Lim, MD, PhDCoralie De Hemptinne, PhDRo’ee Gilron, PhDWhitney Chen, PhDRobert Wilt
NeuropsychologyCaroline Racine Belkoura, PhD
NursingMonica Volz, FNP, MSSusan Heath, MS, RNGina Bringas-Cinco, RNAnnie Li Wong, NPRigzin Lama, RN
NeurologyJill Ostrem, MDCaroline Tanner, MD, PhDMarta San Luciano, MDNicholas Galifianakis, MDMaya Katz, MDIan Bledsoe, MD,MSJames Maas, MD, PHDChadwick Christine, MDMichael Aminoff, MDRobert Edwards, MD, PhDKen Nakamura, MD, PhDAlexandra Nelson, MD, PhDMichael Geschwind, MD, PhDCameron Dietiker, MDNijee Luthra, MD, PhDEthan Brown, MDSamuel Goldman, MDSimon Little, MD, PhDRafael Zuzuarregui, MD
PsychiatryAndrea Seritan, MD
Physical TherapyHeather Bhide, PT
FellowsFay Gao, MDLauren Spiegel, MDAmir Badiei, MDPrarthana Prakash, MDMia Vuong, MDFaiza Butt, MD
Research /Support StaffSarah Wang, PhDJanet AllenYasmeen GonzalezChristine JiuntiJeverly CalaunanKathleen Comyns, MPHCheryl Meng, MPH Farah Kauser, PhDDanilo RomeroVy NguyenEnrique EsteinouRaisa SyedDarel ObonnaMellssa GittingsMaria Loudette BautistaAaron Daley
Social WorkMonica Eisenhardt, LCSWSamuel Yee
ChaplinJudith Long